Is CHN2 p.Val252Ile (c.754G>A) pathogenic?

CHN2 p.Val252Ile (c.754G>A) is classified Uncertain significance in CHN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-05). AlphaMissense: likely benign (0.2731); Ultra-rare (popmax 0.0121%, afr).

How common is CHN2 p.Val252Ile (c.754G>A) in the general population?

CHN2 p.Val252Ile (c.754G>A) is ultra-rare (popmax 0.0121%, afr) (gnomAD).

What do computational predictors say about CHN2 p.Val252Ile (c.754G>A)?

AlphaMissense predicts likely benign (score 0.2731) — an in-silico prediction, not a clinical call.

CHN2 p.Val252Ile

c.754G>A · VCV3492409

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2731 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2731	likely benign
REVEL	0.612	indeterminate
SaProt	LLR -9.82	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 318 kb · p 0.0002 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0121% African / African-American · 9/74,200 alleles

Filtering AF 0.00629% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00527%

Overall 0.00613% 98/1,597,844 alleles · ultra-rare exomes 93/1,445,878 · genomes 5/151,966 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0121%	8,244
European (non-Finnish)	0.00698%	14,320
Remaining individualsnot grpmax-eligible	0.00485%	20,603
South Asian	0.00344%	29,109
East Asian	0.00224%	44,644

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CHN2
Protein: p.Val252Ile
Coding: c.754G>A
MANE Select: NM_004067
Type: single nucleotide variant
Location: chr7:29499881 (GRCh38)
Gene constraint: LOEUF 0.885 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.06 · 1 PDB

Full CHN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHN2 p.Ala201Val Uncertain significance ★ ⚠ same type
CHN2 p.Ala3Thr Uncertain significance ★ ⚠ same type
CHN2 p.Arg290Ser Uncertain significance ★ ⚠ same type
CHN2 p.Arg299Gln Uncertain significance ★ ⚠ same type
CHN2 p.Arg313Thr Uncertain significance ★ ⚠ same type
CHN2 p.Arg39His Uncertain significance ★ ⚠ same type
CHN2 p.Arg404Trp Uncertain significance ★ ⚠ same type
CHN2 p.Arg47Gln Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/chn2-p-val252ile (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown